Next-Gen Oral Therapeutics for Concomitant Clostridioides difficile Infection and IBD

Next-Gen Oral Therapeutics for Concomitant Clostridioides difficile Infection and IBD Biotherapeutics Inc (BTI) is an emerging biotech company that synergistically combines the power of advanced computational modeling with translational experimentation to accelerate the development of novel products for precision medicine and health. Clostridioides difficile infection (CDI) affects almost half a million people in the U.S. yearly, causing 29,000 deaths within 30 days of the initial diagnosis. CDI is trigged by gut microbiome disruption, commonly due to antibiotic usage. However, the standard of care (SOC) is antibiotic-based therapy, leading to high recurrence rates. The incidence of CDI is increased in inflammatory bowel disease (IBD) patients, and is the most common complication in IBD, resulting in increased flares, mortality, and hospitalization days. Managing the treatment of dual IBD and CDI is very challenging and there are limited therapeutic options. The goal of this SBIR Phase 1 application is to develop a novel, host-targeted, antibiotic-sparing oral therapeutic for dual CDI and IBD that targets a novel mechanism of action with no-dose limiting toxicities. We will compare the therapeutic efficacy of our novel drug candidate with FDA-approved therapeutics and determine the effects on the gut microbiome. The Specific Aims of this SBIR Phase 1 are to: AIM 1. Compare the efficacy of a novel oral immunoregulatory therapeutic candidate versus FDA- approved treatments in concomitant CDI and IBD. We will use a DSS-induced and Helicobacter hepaticus model of dual IBD and CDI to evaluate the comparative therapeutic efficacy of our new drug candidate to vancomycin, gut microbiome transplantation (FMT) and anti-TcdB antibody. Endpoints will include mortality, disease activity, weight loss, colonic histopathology and infiltration of inflammatory subsets. AIM 2. Characterize the effects of a novel immunoregulatory therapeutic candidate in modulating gut microbiome dynamics during CDI. Using the DSS-induced mouse model of IBD and CDI we will assess the effects of our novel drug candidate in modulating gut microbiome composition and diversity, and the abundance of C. difficile-resistant strains in comparison to vancomycin and anti-TcdB antibody. We will conduct 16S sequencing, metabolomics analysis and targeted nutrient profiling. Expected outcomes: i) ≥ 30% reduction in histopathological scores; and ii) ≥ 40% increase of alpha diversity; compared to standard of care (SOC). The SBIR Phase II will evaluate combination therapies with standard of care IBD therapeutics in additional preclinical models, complete IND-enabling studies, and file an IND. Commercial Application: This SBIR Phase 1 project will develop a novel anti-microbial free, host-centered oral therapeutic for CDI treatment in IBD and non-IBD, for a market estimated to over $15 billion.